aHUS Therapeutic Drugs – Research & Development (aHUS Pipeline 2017)

The aHUS Alliance presents an overview of a small segment of orphan drug research and development, with the potential for advancements in 2017 that may bring new therapeutic drugs to treat patients with atypical HUS. Research in the field of complement-mediated diseases in 2016 became a faster flowing river of information that sought new levels and touched upon new shores. International research collaboration and translational science appears to increasingly cut across disciplines and medical specialties, providing a continually evolving landscape with expanded potential for advancement in 2017 regarding new therapeutic drugs in development which might hold promise as future treatment options for aHUS patients.

As with most exceptionally rare diseases, atypical hemolytic uremic syndrome (aHUS) is not well known1 by clinicians, although that is beginning to change with the aHUS pediatric global consensus2 in 2015 and conclusions from the 2016 KDIGO global Controversies Conference regarding improved outcomes for patients with aHUS and C3 glomerulopathy3. An additional barrier for those seeking information about aHUS is the variance in spelling4 which is further compounded by the various ways this disease is categorized or grouped in the literature, such inclusion of aHUS research as under the generalized terms “complement mediated diseases” and “thrombotic microangiopathies” (TMA). Those seeking clinical trials open to aHUS patients suffer similar difficulty uncovering information, since 22 studies can be found on www.ClinicalTrials.gov5 utilizing the search term “atypical HUS” with 55 entries found by changing the search term to “aHUS”.

Global investigation and development of innovative therapeutic drugs is a complex process, especially in light of additional challenges for orphan drugs and biopharmaceuticals. Presented here are links to various therapeutic agents in development, as well as research topics and additional disease information which may impact knowledge, provide insights, or affect future developments related to aHUS. Increased knowledge of immune and Inflammatory mechanisms may aide better understanding of aHUS, to include diseases which share a trait in common with the three main clinical characteristics of aHUS: microangiopathic hemolytic anemia (to include red blood cell destruction), acute kidney injury (AKI), and thrombocytopenia (platelet deficiency).6 Eculizumab was approved for therapeutic use with aHUS patients in 20117 but initially was investigated as a complement inhibitor for PNH patients, so it’s logical to keep aware of new information related to that rare disease and additionally also monitor therapeutic drug development and research findings for certain other diseases.

Investigations into novel drug developments for complement-mediated diseases have approached new therapeutic options on all three pathways, targeting different stages and binding sites. The complement system is a critical part of the immune system, with three biochemical arms: classical, lectin (MBL), and alternative pathways. Multiple approaches exist to build a “complement arsenal” 8. With new complement inhibitors under investigation, some target early in the complement cascade (upstream) and others with later intervention points (downstream). Activation of complement pathways and its dysregulation, a hallmark of aHUS activity, plays a central role in many diseases. Research tends toward a growing number of disease associations, along with improved insight into immune cross-talk mechanisms. Since medical and research professionals are much better qualified to present a full review of the literature and to detail specifics of therapeutics under development that may hold promise for aHUS patients, recognize that information here serves merely as a starting point to delve deeper.

See Appendix: Table of Diseases: Potential for Cross-Over to aHUS Research

Advancements in disease knowledge and treatments could be accelerated by collaboration and data sharing, but genomic and clinical data largely remains collected, studied, and held in silos that often isolate information by disease, institution, and/or nation.9 Progress in rare disease research and investigational drug development is understandably hampered due to a core concept of rare diseases, the very small patient populations. Valid issues and barriers exist in the highly competitive field of research as well as throughout the pharmaceutical and biotechnology industries, particularly regarding proprietary information and intellectual property concerns. Privacy rights and informed consent present legal and access challenges on an international stage, and become key considerations for responsible data sharing and collaborative efforts among researchers, nations, rare disease registries, and genomic projects. For those reasons, it is particularly impressive to see effective trans-disciplinary research efforts that involve multi-national, holistic collaborations in rare disease research, at conferences, and for global registries.

As the future of aHUS therapeutic drugs continues to unfold throughout 2017, so will advancements in biotechnology realms. Increasing rates of kidney failure have boosted the need for new and better options, to include expanded exploration of artificial kidneys and biotechnology such as ‘kidneys on a chip’. Genomics, gene editing, and CRISPR technology are hot topics with multiple applications in the rare disease arena, both for research organizations and drug discovery companies. While generic drugs simply copy a chemical compound, creating biosimilar drugs of existing biopharmaceuticals is much more difficult. Since biosimilars and biologics are made from living materials, replication presents special challenges although successful biosimilars may mean lower treatment costs for patients and therefore potential for broader adoption and access. In the 2016 aHUS Global Poll 67% of respondents noted that their specialist or medical team had discussed aHUS treatment cost with the patient and their family, with access to treatment highlighted as a key concern for patients, families, and advocacy groups.

Conferences in the medical, rare disease, and biotech arenas provide a rich source of information in addition to gaining knowledge via a review of the literature. Hints of possible aHUS advancements can be referenced in such diverse areas as inflammatory and immunology research, with new information presented across disciplines at nephrology, hematology, genetic, renal, complement, and other conferences. Given all the information, all the research, all the clinical expertise, we still jointly (and rightly) focus on the same basic goal of improving patient outcomes. At the heart of all areas and all efforts in both research and clinical settings, from bench to bedside, is the patient.

Patient-centered care includes establishing a respectful relationship where patients feel involved, informed, and involved in their care. Much has been written about patient engagement and its value, and patient organizations can help facilitate patient involvement at all stages and with all aspects of research, drug development, and clinical trials. The aHUS Alliance Directory lists known aHUS patient groups and organizations, providing networking assistance to allow those with an interest in aHUS to establish direct connection with various nations and groups around the world. The 2016 aHUS Global Poll, with 233 respondents in 23 nations, provided both data and insight into the aHUS patient experience, amplifying their voice relative to interests, needs, and views on all aspects of treatment and care. Patients and pediatric caregivers offered opinions on a wide range of important topics to include various research areas, drug development, and access to treatment. The aHUS Alliance is sponsoring an “Patients’ Voice: aHUS Research Questions”, to launch on Rare Disease Day 28 February 2017, echoing the 2017 Rare Disease Day theme of “Research” by engaging the aHUS community around the world to state questions about aHUS research.

Connecting scientific and technology advancements to aHUS research helps patients, caregivers, and families learn about their diagnosis and provides background for deeper understanding of discussion they may have with their specialists and care team. Collaboration and connectivity among stakeholders’ efforts was central to the first aHUS patients’ research agenda, resulting in the Orphanet article “An innovative and collaborative partnership between patients with rare disease and industry-supported registries: the Global aHUS Registry” in which the aHUS Alliance revealed a list of priority aHUS research topics within the context of the global registry for aHUS patients. From registries to research, from conferences to clinical trials, consider adding the patient perspective – everything for patients, with patients. Who better than patients to voice opinion about the new therapeutic options, note concerns about drug cost and access, or comment on research directions and priorities? In commerce, one would not bring a product to market without focus groups and a vast understanding of the needs and concerns of the end-user of that product. In 2017, may the coming year be rich with new knowledge, innovative research, broad collaborations and yes – hope for major advancements in therapeutic drugs.

January 2017

L Burke

About the aHUS Alliance

As an international group of aHUS patient organizations, the aHUS Alliance reaches out to provide news and insights into key topics of high interest to the aHUS community through website, Facebook, and Twitter content. Specific groups and nations involved in aHUS advocacy around the world can be viewed in the aHUS Directory, a list of known patient associations or outlets with an aHUS website or social media presence.

Note: Research done for other complement-mediated diseases, or those with similar underlying mechanisms, may provide knowledge to advance aHUS research and therapeutic drug discovery. Listed are some diseases for which future investigations may provide cross-over information for aHUS researchers.